Hereditary Spastic Paraplegia (SPG; OMIM 182600) comprises a group of neurodegenerative disorders characterized by progressive spasticity of the lower limbs. SPG has been classified into pure (uncomplicated) and complex (complicated) forms based on clinical symptoms; patients with complicated SPG exhibit in addition to spasticity of the lower limbs other neurological symptoms, such as mental retardation, retinal changes, peripheral neuropathy, and ataxia. Decreasing age of onset and/or increasing severity in successive generations has also been noted, suggesting anticipation of SPG symptoms. SPG is genetically heterogeneous; autosomal dominant "uncomplicated" SPG families show locus heterogeneity, with linkage reported to chromosomes 2p (SPG4), 14q (SPG4), 14q (SPG3), and thus far a single kindred mapping to 15q (SPG6). A number of studies including our own suggest that the majority of most families are linked to chromosome 2p. In addition, anticipation has been reported for the chromosome 2 locus. Families unlinked to any of the three known loci have also been reported, suggesting that at least one additional major SPG locus. The minimum candidate regions (MCR) reported for SPG4 and SPG3 are a 3 cM interval between D2S352 and D2S367 and a 7 cM interval between D14S288 and D12S281, respectively. The purpose of this project is to continue our longstanding genetic analysis of autosomal dominant SPG. We will prioritize these studies by first attempting to positionally clone the SPG4 locus on chromosome 2p. Once identified we will carry out mutation analysis and phenotype/genotype correlations in conjunction with Cores B and C. Positionally cloning of additional SPG will commence upon successful completion of our chromosome 2 work. In addition, we propose to identify in conjunction with Core C other loci using our unlinked families.